Urea derivatives of tropane, their preparation and their therapeutic application

ABSTRACT

The present invention is related to a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 4 , p, r and   are as defined herein, its preparation, pharmaceutical composition and use as a modulator of the activity of the 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1).

This application is a Divisional of application Ser. No. 12/332,547,filed Dec. 11, 2008, which is a Continuation of InternationalApplication No. PCT/FR2007/001070, filed Jun. 26, 2007, both of which reincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to urea derivatives of tropane, to thepreparation thereof and to the therapeutic use thereof. The presentcompounds modulate the activity of the 11β-hydroxysteroid dehydrogenasetype 1 (11βHSD1) and are of use in the treatment of pathologies in whichsuch a modulation is beneficial, as in the case of metabolic syndrome ornon-insulin-dependant type 2 diabetes.

BACKGROUND OF THE INVENTION

11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) locally catalyzes theconversion of inactive glucocorticoids (cortisone in humans) to activeglucocorticoids (cortisol in humans) in various tissues and organs,mainly the liver and the adipose tissue, but also in the muscles, bones,pancreas, endothelium and ocular tissue and in certain parts of thecentral nervous system. 11βHSD1 acts as a regulator of glucocorticoidaction in the tissues and organs where it is expressed (Tomlinson etal., Endocrine Reviews 25 (5), 831-866 (2004, Davani et al., J. Biol.Chem. 275, 34841 (2000); Moisan et al., Endocrinology, 127, 1450(1990)).

The most important pathologies in which glucocorticoids and theinhibition of 11βHSD1 are involved are indicated below.

A. Obesity, Type 2 Diabetes and Metabolic Syndrome

The role of 11βHSD1 in obesity, type 2 diabetes and metabolic syndrome(also known as syndrome X or insulin resistance syndrome), where thesymptoms include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipodemia (ReavenAnn. Rev. Med. 44, 121 (1993)) is described in many publications. Inhumans, treatment with carbenoxolone (a nonspecific inhibitor of11βHSD1) improves insulin sensitivity in slim volunteer patients and intype 2 diabetics (Andrews et al., J. Clin. Endocrinol. Metab. 88, 285(2003)). Furthermore, mice in which the 11βHSD1 gene has been knockedout are resistant to hyperglycemia induced by stress and obesity, showattenuated induction of liver neoglucogenesis enzymes (PEPCK and G6P)and exhibit an increased sensitivity to insulin in adipose tissue(Kotelevstev et al., Proc Nat. Acad. Sci. 94, 14924 (1997); Morton etal., J. Biol. Chem. 275, 41293 (2001)). Moreover, transgenic mice inwhich the 11β-HSD1 gene has been overexpressed in adipose tissuesexhibit a phenotype similar to that of human metabolic syndrome(Masuzaki et al., Science 294, 2166 (2001)). It should be noted that thephenotype observed exists without any increase in total circulatingglucocorticoids, but is induced by the specific increase in activeglucocorticoids in adipose deposits.

Moreover, new classes of specific 11βHSD1 inhibitors have recentlyemerged:

-   -   arylsulfonamidothiazoles have shown that they improve        sensitivity to insulin and reduce the blood glucose level in        mice exhibiting hyperglycemia (Barf et al., J. Med. Chem. 45,        3813 (2002)). Furthermore, in a recent study, it has been shown        that compounds of this type reduce food intake and also weight        gain in obese mice (Wang et al., Diabetologia 49, 1333 (2006));    -   triazoles have shown that they improve metabolic syndrome and        slow down the progression of atherosclerosis in mice        (Hermanowski-Vosatka et al., J. Exp. Med. 202, 517 (2005)).

B Cognition and Dementia

Slight cognitive problems are common phenomena in elderly individualsand can, in the end, result in the progression of dementia. In the caseof elderly humans just as in the case of aged animals, inter-individualdifferences for general cognitive functions have been linked todifferences in long-term exposure to glucocorticoids (Lupien et al.,Nat. Neurosci. 1, 69, (1998)). Moreover, dysregulation of the HPA(hypothalamic-pituitary-adrenal) axis resulting in chronic exposure ofcertain sub-regions of the brain to glucocorticoids has been proposed ascontributing to the decline of cognitive functions (McEwen et al., Curr.Opin. Neurobiol. 5, 205, 1995). 11βHSD1 is abundant in the brain and isexpressed in many sub-regions, including the hypothalamus, the frontalcortex and the cerebellum (Sandeep et al., Proc. Natl. Acad. Sci. 101,6734 (2004)). Mice deficient in 11βHSD1 are protected againstglucocorticoid-associated hypothalamic dysfunctions which are related toaging (Yau et al., Proc. Natl. Acad. Sci. 98, 4716, (2001)).Furthermore, in studies in humans, it has been shown that theadministration of carbenoxolone improves verbal fluidity and verbalmemory in elderly individuals (Yau et al., Proc. Natl. Acad. Sci. 98,4716, (2001)), Sandeep et al., Proc. Natl. Acad. Sci. 101, 6734 (2004)).Finally, the use of selective 11βHSD1 inhibitors of triazole type hasshown that they prolong memory retention in aged mice (Rocha et al.,Abstract 231 ACS meeting, Atlanta, 25-30 Mar. 2006).

C. Intraocular Pressure

Glucocorticoids can be used topically or systemically for a largevariety of pathologies of clinical opthalmology. One particularcomplication of these treatments is glaucoma induced by the use ofcorticosteroids. This pathology is characterized by elevated intraocularpressure (IOP). In the most serious cases and for non-treated forms, theIOP may result in a partial loss of visual field and possibly evencomplete loss of sight. The IOP is the result of an imbalance betweenthe production of aqueous humor and the drainage thereof. The aqueoushumor is produced in the non-pigmented epithelial cells and drainage iscarried out through the cells of the trabecular network. 11βHSD1 islocalized in the non-pigmented epithelial cells and its function isclearly the amplification of glucocorticoid activity in these cells(Stokes et al., Invest. Opthalmol. Vis. Sci. 41, 1629 (2000)). Thisnotion is confirmed by the observation that the concentration of freecortisol is in great excess relative to cortisone in the aqueous humor(14/1 ratio). The functional activity of 11βHSD1 in the eyes has beenevaluated by studying the action of carbenoxolone in normal volunteers.After seven days of treatment with carbenoxolone, the IOP is reduced by18% (Rauz et al., Invest. Ophthamol. Vis. Sci. 42, 2037 (2001)). Theinhibition of 11βHSD1 in the eyes is therefore predicted to reduce thelocal concentration of glucocorticoids and the IOP, producing abeneficial effect on the treatment of glaucoma and of other sightdisorders.

D. Hypertension

Hypertensive substances derived from adipocytes such as leptin andangiotensinogen have been proposed as being key elements inobesity-related hypertension pathologies (Wajchenberg et al., Endocr.Rev. 21, 697 (2000)). Leptin, which is secreted in excess in transgenicaP2-11βHSD1 mice (Masuzaki et al., J. Clinical Invest. 112, 83 (2003)),can activate various networks of sympathetic neuronal systems, includingthose which regulate arterial pressure (Matsuzawa et al., Acad. Sci.892, 146 (1999)). Furthermore, the renin-angiotensin system (RAS) hasbeen identified as being a determining pathway in the variation ofarterial pressure. Angiotensinogen which is produced in the liver andthe adipose tissue, is a key substrate for renin and is responsible foractivation of the RAS. The plasma angiotensinogen level is significantlyelevated in transgenic aP2-11βHSD1 mice, as are those of angiotensin IIand of aldosterone (Masuzaki et al., J. Clinical Invest. 112, 83(2003)); these elements produce an elevated arterial pressure. Thetreatment of these mice with low doses of an angiotensin II receptorantagonist abolishes this hypertension (Masuzaki et al., J. ClinicalInvest. 112, 83 (2003)). This information illustrates the importance ofthe local activation of glucocorticoids in adipose tissue and the liver,and suggests that this hypertension may be caused or exacerbated by theactivity of 11βHSD1 in these tissues. The inhibition of 11βHSD1 and thereduction of the glucocorticoid level in adipose tissue and/or the liveris therefore predicted as having a beneficial role for the treatment ofhypertension and of associated cardiovascular pathologies.

E. Osteoporosis

Skeletal development and bone functions are also regulated by the actionof glucocorticoids. 11βHSD1 is present in osteoclasts and osteoblasts.The treatment of normal volunteers with carbenoxolone has shown adecrease in bone resorption markers without any change in bone formationmarkers (Cooper et al., Bone, 27, 375 (2000)). The inhibition of 11βHSD1and the reduction of the glucocorticoid level in the bones couldtherefore be used as a mechanism of protection in the treatment ofosteoporosis.

Urea derivatives of tropane which modulate 11βHSD1 activity have nowbeen found.

SUMMARY OF THE INVENTION

The subject of the present invention is compounds corresponding toformula (I):

in which:

-   -   X represents either a carbon, oxygen, sulfur or nitrogen atom or        the —SO₂ group;    -   the dashed-line bond is a single bond or a double bond;    -   R_(1a,b,c,d) and R_(2a,b) which may be identical or different,        each represent a hydrogen or halogen atom; a (C₁-C₅)alkyl;        (C₁-C₅)alkoxy; (C₁-C₅)haloalkyl, hydroxyl; hydroxy(C₁-C₅)alkyl,        (C₁-C₅)alkoxy(C₁-C₅)alkyl; or cyano group; a —COOR₅ group; an        —NR₆R₇ group; a —COOR₅—(C₁-C₅)alkyl group, an        —NR₆R₇—(C₁-C₅)alkyl group, a —CONR₆R₇ group, a —CONR₆R₇—(C₁-C₅)        alkyl group or an —SO₂NR₆R₇ group;    -   (R_(2a))_(p) or (R_(2b))_(r) may also form, with the carbon atom        to which they are attached, a C═O group;    -   R₃ represents a hydrogen atom, a fluorine atom, a (C₁-C₅) alkyl;        (C₁-C₅)alkoxy; alkoxy(C₁-C₅)alkyl; hydroxyl;        hydroxy(C₁-C₅)alkyl; (C₁-C₅)haloalkyl; or cyano group; a —COOR₅        group; an —NR₆R₇ group; a —COOR₅—(C₁-C₅)alkyl group, an        —NR₆R₇—(C₁-C₅)alkyl group, a —CONR₆R₇ group, or a        —CONR₆R₇—(C₁-C₅)alkyl group;    -   R₄ represents:        -   a hydrogen atom or a (C₁-C₅)alkyl group;        -   a (C₃-C₆)cycloalkyl group;        -   a heterocycle;        -   a monocyclic or bicyclic aryl group containing from 5 to 10            carbon atoms;        -   a monocyclic or bicyclic heteroaryl group containing from 2            to 9 carbon atoms;    -   the aryl or heteroaryl group being optionally substituted with 1        to 4 substituents chosen from halogen atoms and the groups:        (C₁-C₅)alkyl; (C₁-C₅)alkoxy; (C₁-C₅)haloalkyl, hydroxyl;        hydroxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl; cyano;        optionally substituted phenyl; optionally substituted benzyl;        —COOR₅; —NR₆R₇; a —COOR₅—(C₁-C₅)alkyl group, an        —NR₆R₇—(C₁-C₅)alkyl group, a —CONR₆R₇ group, a —CONR₆R₇—(C₁-C₅)        alkyl group, an —SO₂NR₆R₇ group, an —NR₆—COR₅ group;    -   p and r, which may be identical or different, are integers equal        to 1 or 2;    -   R₅ represents a hydrogen atom, (C₁-C₅)alkyl group or a        (C₃-C₆)cycloalkyl group;    -   R₆ and R₇, which may be identical or different, each represent a        hydrogen atom, a (C₁-C₅) alkyl group; a (C₃-C₆)cycloalkyl group;        a (C₁-C₅)alkylcarbonyl group; a hydroxymethyl(C₁-C₅)alkyl group;    -   a (C₁-C₅)alkoxymethyl(C₁-C₅)alkyl group; an aryl group or an        —SO₂—R₅ group, or may form, together with the nitrogen atom to        which they are attached, an optionally substituted heterocycle.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may therefore exist in the form of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers and alsomixtures thereof, including racemic mixtures, are part of the invention.

The compounds of formula (I) may exist in the form of endo/exostereoisomers. These endo/exo stereoisomers, and also mixtures thereof,are part of the invention.

The compounds of formula (I) may exist in the form of bases or in a formsalified with acids or bases, in particular pharmaceutically acceptableacids or bases. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are of use, for example, forpurifying or isolating the compounds of formula (I), are also part ofthe invention.

The compounds of formula (I) may also exist in the form of hydrates orof solvates, i.e. in the form of associations or combinations with oneor more water molecules or with a solvent. Such hydrates and solvatesare also part of the invention.

In the context of the present invention, and unless otherwise mentionedin the text:

-   -   the term “halogen atom” is intended to mean: a fluorine, a        chlorine, a bromine or an iodine;    -   the term “a (C₁-C₅) alkyl group” is intended to mean: a linear        or branched, saturated aliphatic group containing 1 to 5        successive carbon atoms. By way of examples, mention may be made        of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        tert-butyl, pentyl, etc. groups;    -   the term “a (C₃-C₆)cycloalkyl group” is intended to mean: a        cyclic alkyl group containing 3 to 6 carbon atoms. By way of        examples, mention may be made of cyclopropyl, methylcyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, etc. groups;    -   the term “a (C₁-C₅)alkoxy group” is intended to mean: an        —O—(C₁-C₅)alkyl radical where the (C₁-C₅) alkyl group is as        defined above;    -   the term “an aryl group” is intended to mean: a monocyclic or        bicyclic aromatic group containing from 5 to 10 carbon atoms. By        way of examples of aryl groups, mention may be made of the        phenyl group, the thiophene group, the furan group or the        naphthalene group;    -   the term “a heteroaryl group” is intended to mean: a monocyclic        or bicyclic aromatic group containing from 5 to 9 carbon atoms        and comprising between 1 and 3 heteroatoms, such as nitrogen,        oxygen or sulfur. By way of examples of heteroaryl groups,        mention may be made of the groups:        -   pyridine        -   pyrazine        -   pyrimidine        -   pyrazole        -   oxadiazole        -   thiazole        -   imidazole        -   benzothiophene        -   quinoline        -   indole;    -   the term “a (C₁-C₅)haloalkyl group” is intended to mean: a        (C₁-C₅)alkyl group as defined above, substituted with 1 to 5        halogen atoms. Mention will, for example, be made of        fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl        or pentafluoroethyl groups;    -   the term “a heterocycle” is intended to mean: an optionally        fused or bridged monocyclic or bicyclic group comprising from 4        to 10 atoms, at least one of which is chosen from oxygen,        nitrogen or sulfur atoms. Mention will, for example, be made of        2,3-dihydrobenzofuran and 1,4-benzodioxane groups;    -   the term “an optionally substituted phenyl group”, “an        optionally substituted benzyl group” or “an optionally        substituted heterocycle” is intended to mean: a phenyl group or        a benzyl group or a heterocycle which is optionally substituted        with one or more of the groups hereinafter: halogen atoms, the        groups: (C₁-C₅) alkyl; (C₁-C₅)alkoxy; (C₁-C₅)haloalkyl,        hydroxyl; hydroxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl; cyano;        phenyl; benzyl; —COOR₅; —NR₆R₇; a —COOR₅—(C₁-C₅)alkyl group, an        —NR₆R₇—(C₁-C₅)alkyl group, a —CONR₆R₇ group, a        —CONR₆R₇—(C₁-C₅)alkyl group or an —SO₂NR₆R₇ group.    -   R_(1a,b,c,d) denotes the groups R_(1a), R_(1b), R_(1c), and        R_(1d), and R_(2a,b) denotes the groups R_(2a) and R_(2b).

Among the compounds of formula (I) which are subjects of the invention,mention may be made of a subgroup of particularly preferred compounds inwhich X is carbon or oxygen, R₁ to R₇, X, p, r and the dashed-line bondbeing as defined above.

Among the latter compounds, particularly preferred compounds of theinvention are compounds of formula (I) in which:

p and r represent 1;

the dashed-line bond represents a single or double bond;

R_(1a,b,c,d) represent hydrogen, or one of the groups R_(1a,b,c,d) is ahalogen and the others are hydrogen;

R_(2a,b) represent hydrogen, or one of the groups R_(2a,b) is a (C₁-C₅)alkyl group, preferably methyl, and the other group R_(2a,b) ishydrogen;

R₃ represents hydrogen;

R₄ in position 4 is chosen from the following aryls or heteroaryls:

-   -   pyridine    -   phenyl    -   pyrazole.

Another group of particularly preferred compounds for the purpose of theinvention corresponds to the derivatives of formula (I) in which Xrepresents the carbon atom and the dashed-line bond represents a doublebond, and R₄ is a phenyl or a pyridine, R_(1a,b,c,d), R_(2a,b), R₃, R₅to R₇, p and r being as defined above.

Another group of particularly preferred compounds for the purpose of theinvention corresponds to the derivatives of formula (I) in which Xrepresents the oxygen atom and the dashed-line bond represents a singlebond, and R₄ is a phenyl or a pyridine, R_(1a,b,c,d), R_(2a,b), R₃, R₅to R₇, p and r being as defined above.

Another group of particularly preferred compounds for the purpose of theinvention corresponds to the derivatives of formula (I) in which Xrepresents the carbon atom and the dashed-line bond represents a singlebond, and R₄ is a phenyl, a pyridine or a pyrazole, R_(1a,b,c,d),R_(2a,b), R₃, R₅ to R₇, p and r being as defined above.

Among the compounds of formula (I) according to the invention, mentionmay be made of:

-   (3,4-dihydro-2H-quinolin-1-yl)-((1S,3S,5R)-3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-((1S,5R)-3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-phenyl-8-azabicyclo-[3.2.1]oct-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-fluoropyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]methanone-   [3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-ethylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   2-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl]benzonitrile-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-fluoropyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(2-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   5-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yl]thiophene-2-carbonitrile-   (3-benzo[b]thiophen-2-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-m-tolyl-8-azabicyclo-[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-isopropylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   4-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yl]benzonitrile-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   3-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl]benzonitrile-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   2-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl]benzamide-   [3-(2-chlorothiophen-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-ethylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(1H-indol-4-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-quinolin-5-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-methoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-methoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(3-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(2,3-dihydrobenzofuran-5-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-p-tolyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(4-hydroxymethylphenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   N-{4-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yl]phenyl}acetamide-   4-[8-(3,4-dihydro-2H-quinoline-1-carbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yl]-N,N-dimethylbenzamide-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(1H-indol-6-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-methoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-isoquinolin-4-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   [3-(2-chloropyridin-4-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-naphthalen-1-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-thiophen-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   [3-(4-aminophenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-fluoropyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-fluoro-2-methylpyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(2-chloro-6-methylpyridin-3-yl)-8-azabicyclo[3.2.1]-oct-2-en-8-yl-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2,6-dimethoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-isoquinolin-5-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(8-methylquinolin-5-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(6-ethyoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2-ethoxypyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(2,6-difluoropyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   [3-(5-chloro-2-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   [3-(2,5-dichloropyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3-benzo[b]thiophen-5-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3-benzo[b]thiophen-7-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(1-methyl-1H-indol-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]methanone-   [3-(6-chloro-4-methylpyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-(3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2H-pyrazol-3-yl)-8-azabicyclo[3.2.1]oct-2-yl]methanone-   (3,4-dihydro-2H-quinolin-1-yl)-[3-(2H-pyrazol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]methanone

In the following, the term “protective group” (Pg) is intended to mean agroup which makes it possible, on the one hand, to protect a reactivefunction such as a hydroxyl or an amine during a synthesis, and on theother hand, to regenerate the intact reactive function at the end ofsynthesis. Examples of protective groups and also of the methods ofprotection and deprotection are given in “Protective Groups in OrganicSynthesis”, Green et al., 3rd edition (John Wiley & Sons, Inc., NewYork).

In the following, the term “leaving group” (Lg), is intended to mean agroup that can be readily cleaved from a molecule by breaking aheterolytic bond with the departure of a pair of electrons. This groupthus can be readily replaced with another group in a substitutionreaction, for example. Such leaving groups are, for example, halogens oran activated hydroxyl group such as a mesyl, tosyl, triflate, acetyl,para-nitrophenyl, etc. Examples of leaving groups and references for thepreparation thereof are given in “Advances in Organic Chemistry”, J.March, 3rd edition, Wiley Interscience, p. 310-316.

In accordance with the invention, the compounds of general formula (I)may be prepared according to the processes hereinafter. In the casewhere X represents a nitrogen atom, it should be substituted either witha group R_(2a,b) (other than H) or with a protective group Pg as definedabove.

In scheme 1, the compounds of formula (IV) can be prepared by reactionbetween the intermediates of formula (II) and a carbonyl of formula(III) having two leaving groups Lg (for example, a chlorine atom, atrichloromethoxy group, a para-nitrophenyl group, an imidazole group ora methylimidazolium group) in the presence of a base such astriethylamine or diisopropylamine, in a solvent such as dichloromethaneor tetrahydrofuran, at a temperature ranging between ambient temperatureand 80° C. The compounds of formulae (I) are obtained by couplingbetween the activated derivatives (IV) and the amines (V) in thepresence or absence of a base such as triethylamine or potassiumcarbonate, in a solvent such as tetrahydrofuran, dichloromethane,acetonitrile or water, at a temperature ranging from ambient temperatureto 100° C.

The heterocycles of general formula (II) are commercially available orcan be prepared by methods described in the literature (“Comprehensiveheterocyclic chemistry”, Katritzky et al., 2nd edition (PergamonPress)).

The heterocycles of general formula (V) are commercially available orcan be prepared by methods described in the literature (Sikazwe et al.,Biorg. Med. Chem. Lett 14, 5739 (2004); Gilbert et al., Biorg. Med.Chem. Lett 14, 515 (2004); Lu et al., Biorg. Med. Chem. Lett 13, 1817(2003)).

Scheme 2 gives details of a synthesis of the compounds of formula (VI)in which the dashed-line bond is a double bond and R₄ represents an arylor heteroaryl group as defined above.

In scheme 2, the heterocycles (VIII), the amine function of which isprotected with a protective group Pg (for example, a Boc or Fmoc group),which have a vinyl sulfonate-A group (for example A may be atrifluoromethyl group or a nonafluorobutyl group), can be prepared byconversion of the ketones (VII) with a sulfonating agent such astrifluorosulfonic anhydride or N-phenyltrifluoromethanesulfonimide inthe presence of a base such as lithium diisopropylamide or lithiumhexamethyl disilazane, in a solvent such as tetrahydrofuran or ethyleneglycol dimethyl ether, at a temperature ranging from −78° C. to ambienttemperature. The heterocycles (X) are obtained by organometalliccoupling between a compound (VIII) and a compound (IX) where Y is aderivative of boron (for example, a boronic acid or a boronic ester) orof tin (for example, a tri(n-butyl)tin) or a halogen atom (for example,bromine or iodine), in the presence of a suitable metal derivative (forexample, palladium, zinc or copper derivatives) in the presence orabsence of a base, such as potassium carbonate, potassium fluoride orsodium phosphate, in a solvent or mixture of solvents, such as dioxane,ethylene glycol dimethyl ether, toluene or water, at a temperatureranging from ambient temperature to 120° C. In a final step, the aminesof formula (VI) are obtained by deprotection of the amine function ofthe compounds of formula (X), by means of methods chosen from thoseknown to those skilled in the art. They comprise, inter alia, the use oftrifluoroacetic acid or of hydrochloric acid in dichloromethane,dioxane, tetrahydrofuran or diethyl ether in the case of a protectionwith a Boc group, and of piperidine for an Fmoc group, at temperaturesranging from −10 to 100° C.

Scheme 3 gives details of a synthesis of the compounds of formula (XI)in which the dashed-line bond is a single bond and R₄ represents an arylor heteroaryl group as defined above.

In scheme 3, the heterocycles (XII) are obtained by hydrogenation of thedouble bond of the heterocycles (X) with a suitable metal catalyst inmethanol or ethanol. In the second stage, the amines of formula (XI) areobtained by deprotection of the amine function of the compounds offormula (XII) by means of methods chosen from those known to thoseskilled in the art. They comprise, inter alia, the use oftrifluoroacetic acid or of hydrochloric acid in dichloromethane,dioxane, tetrahydrofuran or diethyl ether in the case of a protectionwith a Boc group, and of piperidine for an Fmoc group, at temperaturesranging from −10 to 100° C.

Optionally, in scheme 4, the mixture of endo(XIII)/exo(XIV)stereoisomers can be separated by means of flash chromatography, of highpressure liquid chromatography or of recrystallization, otherwise it isused as it is and referred to as mixture (XI).

Scheme 5 shows an alternative pathway for preparing the compounds offormula (I) in which the dashed-line bond is a single bond and R₄represents an aryl or heteroaryl group as defined above; these compoundsare hereinafter known as compounds of formula (XV). In the case where Xrepresents a nitrogen atom, it should be substituted either with a groupR_(2a,b) (other than H), or with a protective group Pg as defined above.

In scheme 5, the amines (XVI) are obtained by deprotection of the aminefunction of the compounds of formula (VIII), by means of methods chosenfrom those known to those skilled in the art. They comprise, inter alia,the use of trifluoroacetic acid or of hydrochloric acid indichloromethane, dioxane, tetrahydrofuran or diethyl ether in the caseof a protection with a Boc group, and of piperidine for an Fmoc group,at temperatures ranging from −10 to 100° C. The compounds of formula(XVII) are obtained by coupling between the active derivatives (IV) andthe amines (XVI) in the presence or absence of a base such astriethylamine or potassium carbonate, in a solvent such astetrahydrofuran, dichloromethane, acetonitrile or water, at atemperature ranging from ambient temperature to 100° C. In the followingstage, the heterocycles (XVIII) are obtained by organometallic couplingbetween a compound (XVII) and a compound (IX) where Y is a derivative ofboron (for example, a boronic acid or a boronic ester), or of tin (forexample, a tri(n-butyl)tin group) or a halogen atom (for example bromineor iodine), in the presence of a suitable metal derivative (for example,a palladium, zinc or copper derivative) in the presence or absence of abase, such as potassium carbonate, potassium fluoride or sodiumphosphate, in a solvent or mixture of solvents, such as dioxane,ethylene glycol dimethyl ether, toluene or water, at a temperatureranging from ambient temperature to 120° C. In a final step, the doublebond of the heterocycles (XVIII) is hydrogenated with a suitable metalin methanol or ethanol, so as to give the derivatives (XV).

Optionally, in scheme 6, the mixture of endo(XIX)/exo(XX) stereoisomerscan be separated by means of flash chromatography, of high pressureliquid chromatography or of recrystallization, otherwise it is used asit is and referred to as mixture (XV).

EXAMPLES

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The numbers of the compoundsexemplified refer back to those given in the table hereinafter whichillustrates the chemical structures and physical properties of somecompounds according to the invention.

Example 11-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride (Compound 4) 1.1: tert-butyl3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

10 ml of a 2.5N solution n-butyl lithium in hexane are added, dropwiseto a solution of 3.73 ml of diisopropylamine in 100 ml oftetrahydrofuran cooled to −60° C., in a 500 ml three-necked flask undernitrogen. After stirring for ¼ hour, 5 g of N-tert-butyloxycarbonylnortropinone in tetrahydrofuran (50 ml) at 0° C. are added. Finally,still at 0° C., 8.32 g of N-phenyltrifluoromethanesulfonimide are added.After stirring for 24 hours at ambient temperature, the tetrahydrofuranis evaporated off and the product is purified by rapid filtration overalumina, using a 2/1 mixture of heptane/ethyl acetate as eluent. 6.13 gof tert-butyl3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylateare obtained.

M+H⁺=358

1.2: 8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethylsulfonatehydrochloride

2.76 g of tert-butyl3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylatein 13 ml of dioxane are placed in a 100 ml round-bottomed flask. 12.8 mlof a 4N solution of hydrochloric acid in dioxane are then carefullyadded. The reaction mixture is stirred for 3 h. The dioxane isevaporated off, to give 2.27 g of 8-azabicyclo[3.2.1]oct-2-ene-3-yltrifluoromethylsulfonate hydrochloride.

M+H⁺=258

1.3:8-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yltrifluoromethanesulfonate

1.13 g of 1,2,3,4-tetrahydroquinoline, 85 ml of dichloromethane and 1.54ml of triethylamine are placed in a 250 ml three-necked flask under anitrogen atmosphere. 0.834 g of triphosgene is added at 0° C., and thereaction is then left to stir at ambient temperature for 4 h. 2.27 g of8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethylsulfonate hydrochlorideand 1.19 ml of triethylamine are subsequently added and the reactionmixture is then refluxed for 18 h. 200 ml of a saturated aqueoussolution of sodium hydrogen carbonate are added and the aqueous phase isextracted three times with dichloromethane. The organic phases arecombined, dried over sodium sulfate and evaporated under reducedpressure. The residue is chromatographed on silica gel with an 8/2mixture of heptane/ethyl acetate. 3.21 g of8-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yltrifluoromethanesulfonate are obtained.

M+H⁺=417

1.4:1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline

0.5 g ofdihydroquinolin-1(2H)-ylcarbonyl)-8-azabicyclo[3.2.1]oct-2-ene-3-yltrifluoromethanesulfonate, 0.419 g of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 0.1 g oflithium chloride, 0.765 g of potassium phosphate, 0.067 g of2′-(dimethylamino)-2-biphenylpalladium(II) chloride dinorbornylphosphineand 4.3 ml of dioxane are introduced into a 10 ml glass tube. The tubeis sealed, and then heated at 100° C. under microwave radiation for 50minutes. Water and ethyl acetate are added. The aqueous phase isextracted three times with ethyl acetate. The organic phases arecombined, dried over sodium sulfate and the solvent is evaporated offunder reduced pressure. The residue is chromatographed on silica gelwith a 3/7 mixture of heptane/ethyl acetate. 0.3 g of1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis obtained.

M+H⁺=346

1.5:1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline

In a high-pressure reactor, under nitrogen, 0.148 g of 5%palladium-on-charcoal is added to 0.240 g of1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinesolubilized in 9 ml of ethanol. The reaction mixture is placed under ahydrogen pressure of 3 atmospheres, at 25° C., and mechanically stirredfor 15 hours. The palladium is filtered off on Whatman paper and washedwith methanol. The solvent is evaporated off, and the residue thenchromatographed on silica gel with an eluent gradient of heptane/ethylacetate (3/7) to heptane/ethyl acetate (2/8). 0.146 g of1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis obtained.

M+H⁺=348.3

1.6:1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride

0.146 g of1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis dissolved in 6 ml of dichloromethane and 4.2 ml of a 4N solution ofhydrochloric acid in dioxane are added. After evaporation, the residueis taken up in ethyl acetate. The precipitate is filtered off and thendried under vacuum. 0.122 g of1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride is obtained.

Melting point=218-220° C.

M+H⁺=348.3

¹H NMR (DMSO, 200 MHz), δ(ppm): 1.4-2 (m, 9H); 2.2-2.44 (m, 1H);2.6-2.78 (t, 2H); 2.9-3.1 (m, 0.4H); 3.2-3.45 (m, 0.6H); 3.5-3.61 (m,2H); 4.1 (sl, 2H); 6.78-6.98 (m, 1H); 7-7.2 (m, 3H); 7.8-7.96 (m, 1H);8.3-8.55 (m, 1H); 8.64-8.9 (m, 2H)

Example 21-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo-[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinoline(Compound 5) 2.11-[(3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl]carbonyl}-1,2,3,4-tetrahydroquinoline

2.87 g of tri(n-butyl)tin 2-pyridine, 0.6 g of lithium chloride, 0.5 gof dihydroquinolin-1(2H)-ylcarbonyl)-8-azabicyclo[3.2.1]oct-2-en-3-yltrifluoromethanesulfonate, 0.249 g of diphenylphosphinepalladium(II)dichloride and 19 ml of tetrahydrofuran are introduced into an 80 mlglass tube. The tube is sealed and then heated at 140° C. undermicrowave irradiation for 1 hour. The reaction mixture is filtered andthen ethyl acetate and a 0.5N aqueous solution of potassium fluoride areadded. The mixture is subsequently filtered, the organic phase is thendried over sodium sulfate and the solvent evaporated off under reducedpressure. The residue is chromatographed on silica gel with a mixture ofheptane/ethyl acetate. 0.73 g of1-[(3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis obtained.

M+H⁺=346

2.21-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo[3.2.1]-oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinoline

In a high-pressure reactor, under nitrogen, 0.5 g of 5%palladium-on-charcoal is added to 0.81 g of1-[(3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinesolubilized in 29 ml of ethanol. The reaction mixture is placed under ahydrogen pressure of 3 atmospheres, at 25° C., and mechanically stirredfor 7 hours. The palladium is filtered off on Whatman paper and washedwith methanol. The solvent is evaporated off and the residue is thenchromatographed on silica gel, with a heptane/ethyl acetate eluentgradient. 0.221 g of1-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-8-yl]-carbonyl}-1,2,3,4-tetrahydroquinolineand 0.141 g of1-{[(3-exo)-3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolineare obtained.

M+H⁺=348.3

2.31-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo[3.2.1]-oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolinehydrochloride

0.221 g of1-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo-[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolineis dissolved in 5.3 ml of dichloromethane, and 6.4 ml of a 0.2N solutionof hydrochloric acid in ether are added. After evaporation, the residueis taken up in ethyl acetate. The precipitate is filtered off and thendried under vacuum. 0.161 g of1-{[(3-endo)-3-pyridin-2-yl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolinehydrochloride is obtained.

Melting point=161-163° C.

M+H⁺=348.3

¹H NMR (CDCl₃, 200 MHz), δ(ppm): 1.36-1.56 (m, 2H); 1.67-1.8 (m, 2H);1.85-2.1 (m, 4H); 2.24-2.4 (m, 2H); 2.7 (t, 2H); 3 (q, 1H); 3.62 (t,2H); 4-4.12 (m, 2H); 6.82 (t, 1H); 6.93-7.09 (m, 3H); 7.15-7.3 (m, 2H);7.43-7.59 (m, 1H); 8.4-8.5 (m, 1H).

Example 31-{[(3-exo)-3-pyridin-2-yl-8-azabicyclo-[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolinehydrochloride (Compound 6)

0.13 g of1-{[(3-exo)-3-pyridin-2-yl-8-azabicyclo-[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolineobtained according to example 2 (part 2.2) is dissolved in 3.1 ml ofdichloromethane, and 3.7 ml of a 0.2N solution of hydrochloric acid inether are added. After evaporation, the residue is taken up in ethylacetate. The precipitate is filtered off and then dried under vacuum.0.101 g of1-{[(3-exo)-3-pyridin-2-yl-8-azabicyclo-[3.2.1]oct-8-yl]carbonyl}-1,2,3,4-tetrahydroquinolinehydrochloride is obtained.

Melting point=178-180° C.

M+H⁺=348.3

¹H NMR (CDCl₃, 200 MHz), δ(ppm): 1.65-2 (m, 10H); 2.7 (t, 2H); 3.09-3.3(m, 1H); 3.2 (t, 2H); 4-4.2, (t, 2H); 6.84 (t, 1H); 6.95-7.23 (m, 5H);7.5-7.67 (m, 1H); 8.45 (d, 1H).

Example 41-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride (Compound 1) 4.1 tert-butyl3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

1 g of tert-butyl3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate,0.975 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 0.24g of lithium chloride, 1.78 g of potassium phosphate, 0.157 g of2′-(dimethylamino)-2-biphenylpalladium(II) chloride dinorbornylphosphineand 10 ml of dioxane are introduced into an 80 ml glass tube. The tubeis sealed and then heated at 100° C. under microwave irradiation for 30minutes. Water and ethyl acetate are added. The aqueous phase isextracted three times with ethyl acetate. The organic phases arecombined and dried over sodium sulfate and the solvent is evaporated offunder reduced pressure. The residue is chromatographed on silica gelwith a mixture of heptane/ethyl acetate. 0.458 g of tert-butyl3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate is obtained.

M+H⁺=387

4.2 tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]-octane-8-carboxylate

In a high-pressure reactor, under nitrogen, 0.17 g of 5%palladium-on-charcoal is added to 0.46 g of tert-butyl3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate solubilized in20 ml of methanol. The reaction mixture is placed under a hydrogenpressure of 3 atmospheres at 25° C., and mechanically stirred for twoand a half hours. The palladium is filtered off on Whatman paper andwashed with methanol. The solvent is evaporated off and 0.46 g oftert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane-8-carboxylate isobtained.

M+H⁺=289

4.3 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane dihydrochloride

2.76 g of tert-butyl3-pyridin-4-yl-8-azabicyclo[3.2.1]octane-8-carboxylate and 4 ml of a 4Nsolution of hydrochloric acid in dioxane are placed in a 10 mlround-bottomed flask. The reaction mixture is stirred for one and a halfhours. The dioxane is evaporated off and 0.341 g of3-pyridin-4-yl-8-azabicyclo[3.2.1]octane dihydrochloride is obtained.

M+H⁺=189

4.41-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline

0.241 g of 1,2,3,4-tetrahydroquinoline, 20 ml of dichloromethane and0.24 ml of triethylamine are placed in a 50 ml round-bottomed flaskunder a nitrogen atmosphere. 0.178 g of triphosgene is added at 0° C.and then the reaction mixture is left to stir at ambient temperature for3 h. 0.34 g of 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane dihydrochlorideand 1.19 ml of triethylamine are subsequently added and the reactionmixture is then refluxed for three hours. 200 ml of a saturated aqueoussolution of sodium hydrogen carbonate are added and the aqueous phase isthen extracted three times with dichloromethane. The organic phases arecombined, dried over sodium sulfate and evaporated under reducedpressure. The residue is chromatographed on silica gel with a 9/1mixture of dichloromethane/methanol. 0.04 g of1-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis obtained.

M+H⁺=348

4.51-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride

0.04 g of1-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolineis dissolved in 1.15 ml of a 0.2N solution of hydrochloric acid inether. After evaporation, the residue is taken up in ethyl acetate. Theprecipitate is filtered off and then dried under vacuum. 0.004 g of1-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinolinehydrochloride is obtained.

Melting point=216-222° C.

M+H⁺=348.2

¹H NMR (DMSO, 200 MHz), δ(ppm): 1.65-1.95 (m, 10H); 2.65 (t, 2H);3.2-3.4 (m, 1H); 3.45 (t, 2H); 4.05 (sl, 1H); 6.75-6.9 (m, 1H); 6.95-7.2(m, 2H); 7.78 (d, 2H); 8.64 (d, 2H).

The table which follows illustrates the chemical structures and thephysical properties of some examples of compounds according to theinvention. In this table:

-   -   in the “salt” column “-” represents a compound in the form of a        free base, while “HCl” represents a compound in hydrochloride        form.

TABLE

LCUVMS Mp Mass No. X

R_(1a) R_(1b) R_(1c) R_(1d) R₃ Endo/exo R₄ Salt (° C.) (amu) Method 1 C— H H H H H Endo/exo

HCl 211-216 1 2 C ═ H H H H H —

HCl 150-176 2 3 C ═ H H H H H —

HCl 218-222 2 4 C — H H H H H Endo/exo

HCl 218-222 2 5 C — H H H H H Endo

HCl 161-163 2 6 C — H H H H H Exo

HCl 178-180 2 7 C — H H H H H Endo/exo

— 133-134 2 8 C — H H H H H Endo/exo

HCl 98-99 2 9 C ═ H H H H H —

— — 379.22 2 10 C ═ H H H H H —

— — 363.24 2 11 C ═ H H H H H —

— — 373.32 2 12 C ═ H H H H H —

— — 370.24 2 13 C — H H H H H —

— — 364.23 2 14 C ═ H H H H H —

— — 379.21 2 15 C ═ H H H H H —

— — 413.23 2 16 C ═ H H H H H —

— — 376.24 2 17 C ═ H H H H H —

— — 401.28 2 18 C ═ H H H H H —

— — 359.29 2 19 C ═ H H H H H —

— — 387.34 2 20 C ═ H H H H H —

— — 370.27 2 21 C ═ H H H H H —

— — 375.26 2 22 C ═ H H H H H —

— — 370.21 2 23 C ═ H H H H H —

— — 375.26 2 24 C ═ H H H H H —

— — 388.21 2 25 C ═ H H H H H —

— — 385.16 2 26 C ═ H H H H H —

— — 373.27 2 27 C ═ H H H H H —

— — 403.23 2 28 C ═ H H H H H —

— — 384.23 2 29 C ═ H H H H H —

TFA — 396.25 2 30 C ═ H H H H H —

TFA — 398.24 2 31 C ═ H H H H H —

— — 363.17 2 32 C ═ H H H H H —

— — 387.22 2 33 C ═ H H H H H —

— — 413.19 2 34 C ═ H H H H H —

— — 363.17 2 35 C ═ H H H H H —

— — 359.18 2 36 C ═ H H H H H —

— — 375.26 2 37 C ═ H H H H H —

— — 402.3  2 38 C ═ H H H H H —

— — 416.26 2 39 C ═ H H H H H —

TFA — 384.23 2 40 C ═ H H H H H —

TFA — 376.19 2 41 C ═ H H H H H —

TFA — 396.23 2 42 C ═ H H H H H —

— — 380.5 2 43 C ═ H H H H H —

— — 395.25 2 44 C ═ H H H H H —

— — 351.15 2 45 C ═ H H H H H —

TFA — 360.26 2 46 C ═ H H H H H —

— — 364.18 2 47 C ═ H H H H H —

— — 378.21 2 48 C ═ H H H H H —

— — 394.18 2 49 C ═ H H H H H —

— — 406.17 2 50 C ═ H H H H H —

TFA — 396.22 2 51 C ═ H H H H H —

TFA — 410.2  2 52 C ═ H H H H H —

TFA — 390.2  2 53 C ═ H H H H H —

TFA — 390.17 2 54 C ═ H H H H H —

— — 382.19 2 55 C ═ H H H H H —

— — 410.18 2 56 C ═ H H H H H —

— — 414.13 2 57 C ═ H H H H H —

— — 401.18 2 58 C ═ H H H H H —

— — 401.17 2 59 C ═ H H H H H —

— — 398.24 2 60 C ═ H H H H H —

— — 394.16 2 61 C ═ H H H H H —

— — 346  2 62 C ═ H H H H H —

— — 346.2  2 63 C — H H H H H endo

— 146-166 2 64 C — H H H H H exo

— 70-81 2 in examples 1 to 64 below: p = r = 1 and R_(2a) = R_(2b) = H

The compounds according to the invention were the subject ofpharmacological tests for determining their inhibitory activity on the11beta-HSD1 enzyme which is an enzyme involved in lipid metabolism orglucose metabolism.

These tests consisted in measuring the in vitro inhibitory activity ofthe compounds of the invention by virtue of an SPA (ScintillationProximity Assay) in 384 well format. The recombinant 11beta-HSD1 proteinwas produced in the yeast S. cerevisiae. The reaction was carried out byincubating the enzyme in the presence of ³H-cortisone and NADPH, in theabsence or in the presence of an increasing concentration of inhibitor.SPA beads coupled to an anti-mouse antibody, pre-incubated with ananti-cortisol antibody, made it possible to measure the amount ofcortisol formed during the course of the reaction.

The inhibitory activity with respect to the 11beta-HSD1 enzyme is givenby the concentration which inhibits 50% of the activity of 11beta-HSD1(IC₅₀).

The IC₅₀ values of the compounds according to the invention are lessthan 1 μM. For example, the IC₅₀ values of compounds No. 4, 7, 13, 28and 55 are, respectively, 0.019 μM, 0.004 μM, 0.122 μM, 0.19 μM and0.534 μM.

It therefore appears that the compositions according to the inventionhave an inhibitory activity on the 11beta-HSD1 enzyme. The compoundsaccording to the invention can therefore be used for the preparation ofmedicaments, in particular for medicaments that inhibit the 11beta-HSD1enzyme.

Thus, according to another of its aspects, a subject of the invention ismedicaments which comprise a compound of formula (I), or an additionsalt of the latter with a pharmaceutically acceptable acid, or else ahydrate or a solvate of the compound of formula (I).

These medicaments are of use in therapy, in particular in the treatmentof obesity, diabetes, insulin resistance, metabolic syndrome, Cushing'ssyndrome, hypertension, atherosclerosis, cognition and dementia,glaucoma, osteoporosis and certain infectious diseases by increasing theefficacy of the immune system.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising a compound according to theinvention as active ingredient. These pharmaceutical compositionscontain an effective dose of at least one compound according to theinvention or a pharmaceutically acceptable salt, a hydrate or a solvateof said compound, and also at least one pharmaceutically acceptableexcipient.

Said excipients are chosen, according to the pharmaceutical form and themethod of administration desired, from the usual excipients which areknown to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I) above, or the optional salt, solvate orhydrate thereof, may be administered in unit administration form, as amixture with conventional pharmaceutical excipients, to animals and tohuman beings for the prophylaxis or treatment of the conditions ordiseases above.

Suitable unit administration forms comprise oral administration formssuch as tablets, soft or hard gel capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal,intraocular, or intranasal administration forms, forms foradministration by inhalation, topical, transdermal, subcutaneous,intramuscular or intravenous administration forms, rectal administrationforms, and implants. For topical application, the compounds according tothe invention may be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises administering an effective dose of a compound according to theinvention or a pharmaceutically acceptable salt or hydrate or solvatethereof, to a patient.

1. A compound of formula (I)

wherein: X is an oxygen, sulfur or nitrogen atom or —SO₂ group;

is a single bond or a double bond; R_(1a), R_(1b), R_(1c), R_(1d),R_(2a) and R_(2b) are independently hydrogen, halogen, (C₁-C₅) alkyl,(C₁-C₅) alkoxy, (C₁-C₅) haloalkyl, hydroxyl, hydroxy(C₁-C₅) alkyl,(C₁-C₅) alkoxy(C₁-C₅) alkyl, cyano, —COOR₅, —NR₆R₇, R₅OOC—(C₁-C₅) alkyl,NR₆R₇—(C₁-C₅) alkyl, —CONR₆R₇, NR₆R₇—CO—(C₁-C₅) alkyl, or —SO₂NR₆R₇; or(R_(2a))_(p) or (R_(2b))_(r) may also form, with the carbon atom towhich they are attached, a C═O group; R₃ is hydrogen, fluorine, (C₁-C₅)alkyl, (C₁-C₅) alkoxy, alkoxy(C₁-C₅) alkyl, hydroxyl, hydroxy(C₁-C₅)alkyl, (C₁-C₅)haloalkyl, cyano, —COOR₅, —NR₆R₇, R₅OOC—(C₁-C₅) alkyl,NR₆R₇—(C₁-C₅) alkyl, —CONR₆R₇, or NR₆R₇—CO—(C₁-C₅) alkyl; R₄ is:hydrogen or (C₁-C₅) alkyl, (C₃-C₆)cycloalkyl, heterocyclyl, (C₅-C₁₀)monocyclic or bicyclic aryl, or (C₂-C₉) monocyclic or bicyclicheteroary, wherein the aryl or heteroary) group is optionallysubstituted with 1 to 4 substituents chosen from the group consisting ofhalogen, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₁-C₅)haloalkyl, hydroxyl,hydroxy(C₁-C₅)alkyl, (C₁-C₅)alkoxy(C₁-C₅)alkyl, cyano, optionallysubstituted phenyl, optionally substituted benzyl, —COOR₅, —NR₆R₇,R₅OOC—(C₁-C₅) alkyl, NR₆R₇—(C₁-C₅) alkyl, —CONR₆R₇, NR₆R₇—CO—(C₁-C₅)alkyl, —SO₂NR₆R₇, and —NR₆—COR₅; p and r, are independently 1 or 2; R₅is hydrogen, (C₁-C₅) alkyl or (C₃-C₆)cycloalkyl; and R₆ and R₇, areindependently hydrogen, (C₁-C₅) alkyl, (C₃-C₆) cycloalkyl, (C₁-C₅)alkylcarbonyl, hydroxymethyl(C₁-C₅)alkyl, (C₁-C₅)alkoxymethyl (C₁-C₅)alkyl, aryl or —SO₂—R₅, or R₆ and R₇, taken together with the nitrogenatom to which they are attached, form an optionally substitutedheterocyclyl; or a salt, solvate or hydrate thereof, or an enantiomer ordiasteroisomer thereof.
 2. The compound according to claim 1, wherein Xis oxygen, or a salt, solvate or hydrate thereof, or an enantiomer ordiasteroisomer thereof.
 3. The compound according to claim 2, wherein: pand r are 1; R_(1a), R_(1b), R_(1c), and R_(1d) are hydrogen, or one ofthe R_(1a), R_(1b), R_(1c), and R_(1d) is halogen and the other R_(1a),R_(1b), R_(1c), and R_(1d) are hydrogen; R_(2a) and R_(2b) are hydrogen,or one of the R_(2a) and R_(2b) is (C₁-C₅) alkyl, and the other ishydrogen; R₃ is hydrogen; and R₄ is pyridyl, phenyl, or pyrazolyl; or asalt, solvate or hydrate thereof, or an enantiomer or diasteroisomerthereof.
 4. The compound according to claim 2, wherein: X is oxygenatom;

is a single bond; and R₄ is phenyl or pyridyl; or a salt, solvate orhydrate thereof, or an enantiomer or diasteroisomer thereof.
 5. Aprocess for preparing the compound according to claim 1, comprisingreacting a compound of formula (IV):

wherein: X, R_(1a), R_(1b), R_(1c), R_(1d), R_(2a), R_(2b), p and r areas defined in claim 1, and Lg is a leaving group; with a compound offormula (V)

wherein: R₃ and R₄ are as defined in claim
 1. 6. A pharmaceuticalcomposition, comprising the compound according to claim 1, or anenantiomer or diasteroisomer thereof, or a pharmaceutically acceptablesalt, hydrate or solvate thereof, in combination with at least onepharmaceutically acceptable excipient.
 7. A pharmaceutical composition,comprising the compound according to claim 2, or an enantiomer ordiasteroisomer thereof, or a pharmaceutically acceptable salt, hydrateor solvate thereof, in combination with at least one pharmaceuticallyacceptable excipient.
 8. A pharmaceutical composition, comprising thecompound according to claim 3, or an enantiomer or diasteroisomerthereof, or a pharmaceutically acceptable salt, hydrate or solvatethereof, in combination with at least one pharmaceutically acceptableexcipient.
 9. A pharmaceutical composition, comprising the compoundaccording to claim 4, or an enantiomer or diasteroisomer thereof, or apharmaceutically acceptable salt, hydrate or solvate thereof, incombination with at least one pharmaceutically acceptable excipient. 10.A method for treating obesity, diabetes, insulin resistance, metabolicsyndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitivedisorder, dementia, glaucoma, osteoporosis or a certain pathologicalcondition requiring activation of the immune system, in a patient inneed thereof, comprising administering to the patient a pharmaceuticallyeffective amount of the compound according to claim 1, or an enantiomeror diasteroisomer thereof, or a pharmaceutically acceptable salt,hydrate or solvate thereof.
 11. A method for treating obesity, diabetes,insulin resistance, metabolic syndrome, Cushing's syndrome,hypertension, atherosclerosis, cognitive disorder, dementia, glaucoma,osteoporosis or a certain pathological condition requiring activation ofthe immune system, in a patient in need thereof, comprisingadministering to the patient a pharmaceutically effective amount of thecompound according to claim 2, or an enantiomer or diasteroisomerthereof, or a pharmaceutically acceptable salt, hydrate or solvatethereof.
 12. A method for treating obesity, diabetes, insulinresistance, metabolic syndrome, Cushing's syndrome, hypertension,atherosclerosis, cognitive disorder, dementia, glaucoma, osteoporosis ora certain pathological condition requiring activation of the immunesystem, in a patient in need thereof, comprising administering to thepatient a pharmaceutically effective amount of the compound according toclaim 3, or an enantiomer or diasteroisomer thereof, or apharmaceutically acceptable salt, hydrate or solvate thereof.
 13. Amethod for treating obesity, diabetes, insulin resistance, metabolicsyndrome, Cushing's syndrome, hypertension, atherosclerosis, cognitivedisorder, dementia, glaucoma, osteoporosis or a certain pathologicalcondition requiring activation of the immune system, in a patient inneed thereof, comprising administering to the patient a pharmaceuticallyeffective amount of the compound according to claim 4, or an enantiomeror diasteroisomer thereof, or a pharmaceutically acceptable salt,hydrate or solvate thereof.